Composition of matter



Patented Sept. 8, 1942 COMPOSITION OF MATTER Robert S. Shelton, Mariemont, Ohio, assignor to The Wm. S. Merrell Company, Cincinnati, Ohio, a corporation of Delaware No Drawing. Application August 2, 1939,

Serial No. 287,959

Claims.

This invention relates to compositions of matter for controlling micro-organisms, including bacteria, fungi, and the like, and/or mitigating their effects; and more especially to compositions -in which some or all of the following properties are utilized: bactericidal, antiseptic, fungicidal, bacteriostatic, prophylactic and to novel chemical compounds having such properties. The invention relates particularly to such compositions which possess some or all of the aforementioned properties to a marked degree and which comprise one or more quaternary ammonium compounds.

Prior to my invention it has been suggested to use certain amines and quaternary ammonium compounds for bactericidal, fungicidal and general disinfecting purposes; and it has also been suggested that, when quaternary ammonium compounds contain, attached to the nitrogen, besides other organic radicals, at least one high molecular weight aliphatic hydrocarbon radical, such compounds may display bactericidal and fungicidal properties. Quaternary ammonium compounds possessing such bactericidal and fungicidal properties have been tested only to a limited extent.

The present invention aims to provide compositions of matter belonging to the general class of quaternary ammonium compounds which will be more eflicacious as bactericidal, antiseptic, fungicidal and bacteriostatic agents than those heretofore available and which are, in general, safer than antiseptics heretofore in general use.

I have found by extensive experiments and tests with compositions containing quaternary ammonium compounds that compositions containing a cetyl trimethyl ammonium salt or hydroxide or similar compositions are most survprisingly efiicacious for the purposes of this invention, as expressed above, being at the same time extremely effective against the undesirable micro-organism, having very low and practically negligible toxicity in effective concentrations and having a penetrating power which is often of great practical importance in compositions of my invention.

The positive ion constituent 'used in the cetyl trimethyl ammonium compound may be any which forms a soluble compound and which does not itself have objectionable properties either alone or by interaction with other ingredients of the composition in which the ammonium compound is used. Among those which may be used satisfactorily are, for example: OH, -C1, -Br, -I, --NO3, =SO4, =CO3, E1 04, OCOCH3, OCOCsH5, -OCOC6H4OH, methosulfate, etho-sulfate and similar ions, the dicarboxylic and tricarboxylic acids such as citric and tartaric, and the lower fatty acids; polyvalent' acid radicals may combine several similar quaternary ammonium groups of the above specified type into a single molecule or one such group may be combined with the acid while the remaining valences of the acid ion are satisfied by hydrogen or'a different cation or group, especially by a low molecular weight organic group, as in the metho-sulfates. Anions which forms insoluble ammonium compounds, particularly the higher fatty acids such as are used in ordinary soaps are not recommended either as the original anion of the ammonium compound or in any ionized ingredient of the same composition.

Among the compounds which have been found to be useful for purposes of my invention are the following:

Aliphatic quaternary ammonium salts Chemical name Critical killing dilution Phenol coefiicient Approximate water E. typhi Staph. aureus E. tuphi Staph. aureua solublhty All the compounds given in the abovelist were prepared from a high purity commercial cetyl alcohol which actually contained small amounts of stearyl and myristyl alcohols as well. Parallel tests with a number of these compounds carefully purified to eliminate the stearyl and myristyl compounds have shown in every case much higher killing dilutions. Moreover, as these impurities are not absolutely uniform, some allowance needs to be made in comparing values for different compounds.

The killing dilutions are for solutions in a menstruum of 50% alcohol, 40% water, acetone. The Phenol coefficient is a convenient index obtained by dividing the critical killing dilution by the critical killing dilution of phenol for'the same organism.

It should be understood that these are only examples given as indications in order to assist others in choosing the best compounds and .perhaps discovering better compounds within the scope of my invention.

It will be understood, of course, that the figures given for activity against the two organisms named cannot be taken as absolute, since they will vary to some degree from test to test with variations in the cultures used; and I have found also that impurities present may have a substantial influence on the exact figure obtained by such a test, although it is an advantage of these compositions that they retain strong activity in the presence of substances which would normally occur during use.

As will be seen from the above figures, these compositions are among the most active thus far discovered, and at the same time they are among the best with respect to low toxicity to humans and animals and with respect to retention of activity in the presence of carbohydrates, especially sugars, proteins, serum or other substances with which such micro-organisms are commonly found in their active life. Using Staphylococcus aureus and Bacillus typhosus as the test organisms it was found, for example, that slightly impure cetyl trimethyl ammonium bromide with 10% by volume of sterile serum added to the diluted germicide completely killed the test organisms in 10 minutes in the following dilutions:

This test also illustrates another valuable quality-the relative immunity of these compositions to acidity and alkalinity. This quality and particularly the relative immunity to presence of calcium and magnesium are especially important in tooth pastes, tooth powders, and antiseptic cleaning compositions for general use, in all of which an alkaline reaction may be important.

These qualities make it possible to use compositions including these quaternary ammonium compounds in compositions which contain flavoring, coloring, therapeutic or healing ingredients; and the compositions of my invention may also be used as preservatives in all kinds of materials,

I A per cent.

including fruits and vegetables, grains, etc., wood, clothing, adhesives, biological materials, and in general wherever organic decomposition or putrefaction might occur. When'used on fruits or vegetables it is found that their penetrating and emulsifying power assists in removal of spray residues as well as assuring destruction of decay infections.

In their use as general antiseptics their immunity to acids and alkalies is very important, and also their immunity to iron salts, calcium salts, and others which may be encountered in normal disinfecting uses.

Tests that have been made, especially with cetyl trimethyl ammonium bromide, show that these compounds have a remarkable detoxifying action even in fairly dilute solutions. It was observed, for example, that when 0.25 cc. 'of a 1:1,000 cetyl trimethyl ammonium bromide was added to 0.3 cc. of a standardized 1:1,000 tetanus toxin and injected subcutaneously into 325-350 gm. guinea pigs, that the animals showed no appearances of paralysis or death after 5 days observation, while the control guinea pigs when injected with 0.3 cc. of the 1:1,000 standardized tetanus toxin under the same conditions all died within 70 hours. This shows that the above described compounds have unusual detoxifying action in extremely dilute solutions, so that they may at the same time be used to kill or control infection and to counteract pois'ons resulting from the infection. This test may be compared with other detoxifying compounds such as formaldehyde, halogen and hydroxy compounds of salicyclic acid and other derivatives which show comparable detoxifying action only in high concentrations, e. g., in the neighborhood of In the concentration required for disinfection and purification processes they do not injure or stain the human skin and may, therefore, be used for disinfecting the skin, particularly the hands. Furthermore, it has been observed that these compounds in dilutions of 1 to 1,000 and less have a low surface tension for the most part in the range between 30-40 dynes/cmf", thus insuring good penetration when used as skin antiseptics.

The ammonium compounds of the present invention may be used in substance as well as in solution or emulsion and, if desired, in admixture with each other and/or with other active or inert substances such as powder, ointment bases, creams, etc.

These compounds have the further advantage that they show definite bactericidal action in vegetable oils. It'has also been observed that these compounds are soluble to a certain extent in vegetable oils, such as olive or almond oils and that the presence of a small amount of benzyl alcohol greatly increases their solubility in oil, for example, cetyl trimethyl ammonium bromide is soluble 1:100 in a solution containing benzyl alcohol, almond oil and petrolatum. Hence these compounds will be of desirable use in rendering ointment bases bactericidal, for example the common petrolatum type of ointments/ In addition to their use in the oil soluble ointment type, we also find that they have decided germicidal action in water soluble jellies, for example, cetyl trimethyl ammonium bromide 1:5,000 in a tragacanth base gives definite germicidal actionto this type of jelly.

It is not necessary that other ingredients should be used, but generally we find that a simple water solution or tincture will be most useful as a general antiseptic,

one very valuable composition, for example, is an aqueous solution of cetyl trimethylammonium bromide diluted 1:1,000. This may be further diluted for use in cleansing or dressing wounds, for cleaning and sterilizing solutions, for use as a mouth wash, etc. For hospitals and other users who prefer more concentrated solutions, e. g., to save storage space, I may supply an aqueous solution cetyl trimethyl ammonium salicylate in dilution of 1:250 or less. Thisllatter solution is a viscous liquid and in lower dilutions approaches even a jelly condition, but for actual use these will ordinarily be diluted, e. g.,

with from -100 times-its weight of water, so

that the final solution is entirely watery.

For treating wounds and skin infections and for disinfecting instruments which are subject to rusting, a tincture is very useful, for example, cetyl trimethyl ammonium salicylate1:1,000 in 30-40% ethyl alcohol. A composition very useful for mouthwash and similar purposes is a solution of cetyl trimethyl ammonium salicylate 110,000 in 18-20% ethyl alcohol with aromatic oils added for flavoring.

Other illustrative compositions in which any of these quaternary ammonium germicides may be used are:

MoU'rH WASH Per cent Germicide .02-.04 Boric acid 1 Alcohol 20-30 Flavor As required Color As required Water 1;. s 100 SKIN ANTISEPTIC Germicide .1-.5 Dye As required Alcoh'ol 40-50 7 Water (1. s 100 CoUoH DROPS Germicide .1 Aromatics As require Sugar q, s 100 LIPSTICK Germicide .1 Beeswax"; 33 Lard 12 Castor nil 12 Perfume and color q. s As required I DENTIFBICE (Paste or powder) Germicide .1 CaCOz 50 Tricalclum phosphate 25 Magnesium carbonate (or hydroxide) 24 Saccharin and flavor; .9 Wetting agent 1 .NOSE DROPS Germicide .04-.02 Ephedrine S04 1 Dextrose 4 Water q. s 100 GERMICIDAL OINTMENT Germicide 0.1 Hydrous lanolin 50.0

Petrolatum 50.0

I 3 Aurrsar'rrc Mamca'ran Skin Cam I Germicide 0.1 Giyceryl monostearate 10.0 Glycerin I Water 85.0

' LUBEICATING- J my Germicide 0.1

Tragaca r 1.0 Glycerin. 15.0 Water q. s 100 7/ These, of course, are only examples; and it should be understood that their proportions can be varied substantially and that numerous other types of compositions are within the scope of the invention. In dentifrices and'mouthwashes the sugar and acid immunity of the germicide are especially important qualities in view of the recent evidence that dental caries is due to growth of lactic acid bacillus. In oil ,basecompositions, the emulsifying or surface tension reducing quality of these germicides is of utmost importance, because it breaks down the barrier of the interface and allows the germicide in the oil solution to become effective in the body fluids and/or the cell fluids of the organisms against which they are used.

These germicides also lend themselves well to germicidal hand cleaners'in which a wetting or "the extent'of 1 to 10%, or a crude quaternary ammonium compound of the type above described may serve both as the detergent wetting agent and as antiseptic when mixed with a suitable carrier.

The compounds of my present invention also have the valuable property of forming remarkably stable dispersions of colloidal metals and insoluble salts. This has been found especially valuable in compositions which combine the valuable therapeutic properties of colloidal silver or colloidal silver salts with the remarkable germicidal properties of these quaternary ammonium compounds.

The .compositions contemplated by the present invention are made conveniently by chemical methods known to those skilled in the art, for example, by reacting upon tri-methyl amine with a reactive cetyl halide.

Alternatively, cetyl dimethyl amine may be reacted with methyl halide, sulfate, acetate, etc., to form the same type of ammonium salt. It has also been observed that the corresponding halides, sulfates, nitrates, salicylates, benzoates, acetates, tartrates, metho-sulfates, etc., can easily be prepared by a prolonged boiling of the bromide in an organic solvent with the corresponding salt of the alkali, alkaline earth or heavy metal. By the above reactions high molecular weight quaternary ammonium compounds are obtained which, in general, depending upon the acid radicals, readily dissolve in water, forming stable,

odorless, colorless and relatively non-toxic solutions.

Example No. 1

The raction is effected between approximately equimolar parts by weight of trimethylamine (33% solution in MeOH) (a slight excess often is advisable) and cetyl bromide at room temperature. After cooling, the crystalline material is filtered off and recrystallized from ethyl acetate. The cetyl-trimethyl ammonium bromide thus obtained forms colorless plates, melting at 235"- 237" C. and is readily soluble in water.

' Example No. 2

Equimolar parts by weight of trimethylamine (35% solution in methyl alcohol) and cetyl chloride are heated together in a pressure flask at 100 C. The mixture is worked up as in Example I No. 1. The resulting cetyl-trimethyl ammonium chloride is a white crystalline solid, very soluble in water,

Example No. 3

Equimolar parts of silver sulfate and cetyl trimethyl ammonium bromide are heated for ten hours inboiling'alcohol. The resulting cetyl trimethyl ammonium sulfate may be separated from the silver bromide by filtration. Other salts may be formed from the halides in a similar way, e. g., salicylate, tartrate, benzoate, nitrate, metho-sulfate, etc.

Example No. 4

One mol of cetyl trimethyl ammonium bromide dissolved in alcohol is refluxed with 1 mol of silver nitrate for four hours, then allowed to cool. The silver bromide is filtered off and the alcoholic solution concentrated and precipitated with ether. The cetyl trimethyl ammonium nitrate is filtered off and recrystallized from ethyl acetate. In a similar manner the cetyl trimethyl ammonium sulfate, metho-sulfate, benzoate, salicylate, tartrate, and acetate are prepared by refluxing in alcohol, molar proportions of cetyl trimethyl ammoniumbromide and the sodium or silver salt of the corresponding organic acid.

' Example No. 5 7

One mol of cetyl dimethylamine is allowed to Example No. 6

Equimolar proportions of cetyl trimethyl ammonium chloride and dimethyl sulfate are heated for about 24 hours at C. with distillation of the methyl chloride formed. The cetyl trimethyl ammonium metho sulfate formed is separated and recrystallized from ethyl alcohol or ethyl acetate. Thissame method may be used also for other alkyl-polybasic acid salts of the ammonium compounds and other salts than the chloride, e. g., other halides, nitrates, etc., may be used provided only that the temperature of heating is chosen so that the ammonium salt and the alkyl salt used are not very volatile, whereas, thealkyl salt formed is sufficiently volatile so that it is readily distilled off from the reacting mixture.

The word inhibiting as used in the following claims is intended to inclu'de the killing of micro-organisms as well as rendering them inactive or harmless, e. g. as in bacteriostatic action.

This application. is a continuation in part of my prior copending application Serial No. 222,448, filed August 1, 1938.

What I claim is:

1. A micro-organism inhibiting composition which comprises as the essential active ingredi- ROBERT S. SHELTON.

composition- 

